US11945822B2ActiveUtilityPatentIndex 47
Pyrazolo-triazine and/or pyrazolo-pxrimidine derivatives as selective inhibitor of cyclin dependent kinase
Est. expiryApr 11, 2038(~11.8 yrs left)· nominal 20-yr term from priority
Inventors:NAM KIYEANKIM JAESEUNGJEON YEEJINYU DONGHOONSEO MOOYOUNGPARK DONGSIKEICKHOFF JANZISCHINSKY GUNTHER
C07D 487/04A61P 35/00A61P 35/02C07D 519/00A61P 29/00A61P 31/00A61P 37/00A61K 31/53A61K 31/519
47
PatentIndex Score
0
Cited by
27
References
20
Claims
Abstract
The present invention relates to pyrazolo[1,5-a][1,3,5]triazine and pyrazolo[1,5-a]pyrimidine derivatives and/or pharmaceutically acceptable salts thereof, the use of these derivatives as pharmaceutically active agents, especially for the prophylaxis and/or treatment of cell proliferative diseases, inflammatory diseases, immunological diseases, cardiovascular diseases and infectious diseases. Furthermore, the present invention is directed towards pharmaceutical compositions containing at least one of the pyrazolo[1,5-a][1,3,5]triazine and pyrazolo[1,5-a]pyrimidine derivatives and/or pharmaceutically acceptable salts thereof.
Claims
exact text as granted — not AI-modifiedThe invention claimed is:
1. A compound having general formula I
wherein
X is, independently at each occurrence, selected from CH and N;
L 1 is either absent or independently, at each occurrence, selected from the group consisting of —NH—, —NH(CH 2 )—, —NH(C═O)—, —NHSO 2 —, —O—, —O(CH 2 )—, —(C═O)—, —(C═O)NH— and —(C═O)(CH 2 )—;
Q is, independently at each occurrence, selected from the group consisting of C3-C8 cycloalkyl, aryl, heteroaryl, heterocyclyl, and C1-C6 alkyl, wherein C1-C6 alkyl is substituted with one or two of —OR 5 , —N(R 5 )R 5 , aryl, heteroaryl and heterocyclyl,
C3-C8 cycloalkyl can be substituted with one or two of R 3 and R 4 and —(C═O)R 5 , heterocyclyl can be substituted with one or two of R 3 and R 4 and —(C═O)R 5 , aryl or heteroaryl can be substituted with one or two of C1-C6 alkyl, —OR 5 , —N(R 5 )R 5 , —(C═O)R 5 , halogen, heteroaryl and heterocyclyl;
R 1 is hydrogen;
R 2 is, at each occurrence, independently selected from the group consisting of C1-C6 alkyl, C3-C10 cycloalkyl, —CN, —(C═O)CH 3 , —NR 9 R 12 and C1-C3 haloalkyl, any of which is optionally substituted;
R 3 is independently, at each occurrence, selected from the group consisting of hydrogen, —OR 5 , halogen, —N(R 5 )R 5 , —NR 9 R 12 , —NH(C═O)R 5 , —(C═O)NH 2 , aryl, heteroaryl, heterocyclyl, C1-C6 alkyl and C1-C6 alkyl substituted with —OH or —NH 2 ;
R 4 is, independently, at each occurrence, selected from the group consisting of hydrogen, halogen, —OR 5 , —N(R 5 )R 5 , (═O), aryl, heteroaryl, heterocyclyl, C1-C6 alkyl and C1-C6 alkyl substituted with —OH or —NH 2 ;
R 5 is, at each occurrence, independently selected from the group consisting of hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C3 haloalkyl, heteroaryl optionally substituted with one or two of halogen, —OR 11 , —N(R 11 )R 11 , and C1-C6 alkyl optionally substituted with —OH or —NH 2 , heterocyclyl optionally substituted with one or two of halogen, —OR 11 , —N(R 11 )R 11 , C1-C6 alkyl and C1-C6 alkyl substituted with —OH or —NH 2 ;
Z is
wherein
X 1 is CR 24 ;
X 2 is CR 25 ;
R 6 is, at each occurrence, independently selected from hydrogen, and any structure of the following group B;
R 7 is, at each occurrence, independently selected from the group consisting of hydrogen, C1-C6 alkyl, and any structure of the following group C;
R 8 and R 10 are, at each occurrence, independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C3 haloalkyl, —NH 2 , —OH, —OR 5 , —CN, —(C═O)R 5 , —(C═O)OR 5 , —(C═O)NH 2 , —(C═O)NHR 21 , —CH 2 (C═O)NHR 21 , —NH(C═O)R 13 , —NHS(═O) 2 R 5 , —S(═O) 2 NH 2 , —S(═O) 2 NHR 21 , and C1-C6 alkyl substituted with —OH, —OR 5 or —NHR 9 ;
R 9 is, at each occurrence, independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C3 haloalkyl, —OR 5 , —CN, C3-C10 cycloalkyl, C3-C10 heterocyclyl and C1-C6 alkyl substituted with —OH or —OR 5 ;
R 11 is, at each occurrence, independently selected from the group consisting of hydrogen, C1-C6 alkyl and C3-C10 cycloalkyl;
R 12 is, at each occurrence, absent or independently selected from the group consisting of C1-C6 alkyl optionally substituted with —OR 5 or —N(R 5 )R 5 , benzyl optionally substituted with one to four halogens or C1-C3 alkyls, C3-C9 heteroaryl optionally substituted with one to four halogens or C1-C3 alkyls, C3-C6 heterocyclyl optionally substituted with C1-C3 alkyl, and C6-C10 aryl optionally substituted with one to four halogens and/or one to four —NH(C═O)R 13 ;
R 13 is, at each occurrence, independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkyl substituted with —CN, —OH, —OR 5 , —NH 2 , —NHR 5 or —N(R 5 )R 5 and C3-C10 cycloalkyl;
R 14 and R 15 are, at each occurrence, independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C6 alkyl substituted with —OH or —NH 2 , C3-C10 cycloalkyl, —(C═O)R 5 , —(C═O)NHR 21 , —C(R 9 )(R 11 )OR 21 , —NH(C═O)R 21 , —NR 9 R 21 , —OR 21 , —OC(R 9 )(R 11 )(R 21 ), C3-C10 heterocyclyl, C3-C10 heterocyclyl substituted with R 4 , C3-C10 heteroaryl substituted with one to four halogens or C1-C3 alkyl, C6-C10 aryl, and aryl substituted with —(C═O)R 5 , —(C═O)OR 5 , —(C═O)NH 2 , —(C═O)NHR 21 , —CH 2 (C═O)NHR 21 , —NH(C═O)R 13 , —NHS(═O) 2 R 5 , —S(═O) 2 NH 2 or —S(═O) 2 NHR 21 ;
R 16 is, at each occurrence, independently selected from the group consisting of hydrogen, C1-C6 alkyl, —(C═O)R 13 and C1-C6 alkyl substituted with —OR 5 ;
R 17 , R 18 , R 19 and R 20 are, at each occurrence, independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C3 haloalkyl, C6-C10 aryl, —CN, —CHCF 3 NR 9 R 11 , —OH, —OR 21 , —NO 2 , —(C═O)R 5 , —(C═O)OR 5 , —(C═O)NH 2 , —(C═O)NHR 21 , —NH(C═O)R 13 , —NHR 5 , —NHS(═O) 2 R 5 , —S(═O) 2 NH 2 , —S(═O) 2 NHR 21 and C1-C6 alkyl substituted with —CN, —OH, —OR 5 , —(C═O)NHR 5 , —NH 2 , —NH(C═O)R 5 , —NHR 5 or —N(R 5 )R 5 ;
R 21 is, at each occurrence, independently selected from the group consisting of C3-C10 cycloalkyl, C1-C3 haloalkyl, benzyl, C1-C6 alkyl optionally substituted with —CN, —OH, —OR 5 , —NH 2 , —NHR 5 or —N(R 5 )R 5 , aryl optionally substituted with halogen or C1-C3 haloalkyl, C3-C10 heteroaryl substituted with one to four halogens or C1-C3 alkyl and C3-C10 heterocyclyl optionally substituted with R 4 ;
R 22 and R 23 are, at each occurrence, independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C3 haloalkyl, —OH, —OR 5 , —CN and C1-C6 alkyl substituted with —OH, —OR 5 or —NHR 9 ;
R 24 and R 25 are, at each occurrence, independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C3 haloalkyl, —NH 2 , —OH, —OR 5 , —CN, —(C═O)R 5 , —(C═O)OR 5 , —(C═O)NH 2 , —(C═O)NHR 21 , —CH 2 (C═O)NHR 21 , —NH(C═O)R 13 , —NHS(═O) 2 R 5 , —S(═O) 2 NH 2 or —S(═O) 2 NHR 21 and C1-C6 alkyl substituted with —OH, —OR 5 or —NHR 9 ;
with the proviso that when Z is
then one of R 6 and R 7 is not H;
with the proviso that when Z is
then one of R 6 and R 22 is not H;
with the proviso that when R 6 is
then one of R 14 and R 15 is not H, and if R 14 is H, then R 15 is not Cl;
wherein, if R 1 is H, R 2 is CH(CH 3 ) 2 , L 1 is absent, Q is heterocycyl substituted with R 3 and R 4 , R 3 is N(R 5 )R 5 , R 4 is H, R 5 is H, X is N, Z is phenyl, R 7 is H, R 8 is H, R 9 is H and R 10 is H, then R 6 is not 1H-pyrazole;
wherein, if R 1 is H, R 2 is CH(CH 3 ) 2 , L 1 is O, Q is heterocycyl substituted with R 3 and R 4 , R 3 is CH 3 , R 4 is H, X is N, Z is phenyl, R 7 is H, R 8 is H, R 9 is H and R 10 is H, then R 6 is 1H-pyrazole;
wherein, if R 1 is H, R 2 is CH(CH 3 ) 2 , L 1 is —(C═O)—, Q is heterocycyl substituted with R 3 and R 4 , R 4 is H, X is N, Z is phenyl, R 6 is 1H-pyrazole, R 7 is H, R 8 is H, R 9 is H and R 10 is H, then R 3 is not H;
wherein, if R 1 is H, R 2 is CH(CH 3 ) 2 , L 1 is —(C═O)—, Q is heterocycyl substituted with R 3 and R 4 , R 3 is N(R 5 )R 5 , R 4 is H, R 5 is H, X is N, Z is phenyl, R 7 is H, R 8 is H, R 9 is H and R 10 is H, then R 6 is not 1H-pyrazole,
wherein, if R 1 is H, R 2 is CH(CH 3 ) 2 , L 1 is O, Q is heterocycyl substituted with R 3 and R 4 , R 3 is H, R 4 is H, X is N, Z is phenyl, R 7 is H, R 8 is H, R 9 is H and R 10 is H, then R 6 is not 1H-pyrazole;
wherein, if R 1 is H, R 2 is CH(CH 3 ) 2 , L 1 is O, Q is C3-C8 cycloalkyl substituted with R 3 and R 4 , R 3 is N(R 5 )R 5 , R 4 is H, R 5 is H, X is N, Z is phenyl, R 7 is H, R 8 is H, R 9 is H and R 10 is H, then R 6 is not 1H-pyrazole;
wherein, if R 1 is H, R 2 is CH(CH 3 ) 2 , L 1 is NH, Q is heterocycyl substituted with R 3 and R 4 , R 3 is H, R 4 is H, X is N, Z is phenyl, R 7 is H, R 8 is H, R 9 is H and R 10 is H, then R 6 is not 1H-pyrazole;
wherein, if R 1 is H, R 2 is CH(CH 3 ) 2 , L 1 is NH, Q is C3-C8 cycloalkyl substituted with R 3 and R 4 , R 3 is N(R 5 )R 5 , R 4 is H, R 5 is H, X is N, Z is phenyl, R 7 is H, R 8 is H, R 9 is H and R 10 is H, then R 6 is not 1H-pyrazole;
wherein, if R 1 is H, R 2 is CH(CH 3 ) 2 , L 1 is O, Q is heterocycyl substituted with R 3 and R 4 , R 3 is H, R 4 is H, X is N, Z is phenyl, R 7 is H, R 8 is H, R 9 is H and R 10 is F, then R 6 is not 1H-pyrazole;
wherein, if R 1 is CH 3 , R 2 is CH(CH 3 ) 2 , L 1 is O, Q is heterocycyl substituted with R 3 and R 4 , R 3 is H, R 4 is H, X is N, Z is phenyl, R 7 is H, R 8 is H, R 9 is H and R 10 is H, then R 6 is not 1H-pyrazole;
wherein, if R 1 is H, R 2 is CH(CH 3 ) 2 , L 1 is O, Q is heterocycyl substituted with R 3 and R 4 , R 3 is CH 3 , R 4 is H, X is N, Z is phenyl, R 7 is H, R 8 is H, R 9 is H and R 10 is H, then R 6 is not 1H-pyrazole;
wherein, if R 1 is CH 3 , R 2 is CH(CH 3 ) 2 , L 1 is O, Q is heterocycyl substituted with R 3 and R 4 , R 3 is H, R 4 is H, X is N, Z is phenyl, R 6 is H, R 7 is OR 12 , R 8 is H, R 9 is H and R 10 is H, then R 12 is not CH 3 ;
or an enantiomer, stereoisomeric form, mixture of enantiomers, diastereomer, mixture of diastereomers, racemate of the above compounds, or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1 , wherein R 14 , R 15 , R 17 , R 18 , R 19 or R 20 is phenyl.
3. The compound according to claim 1 ,
wherein R 1 is hydrogen and the compound has the general formula II
wherein X, Q, L 1 , R 2 and Z are as defined in claim 1 .
4. The compound according to claim 1 , having the general formula III
wherein X, L 1 , R 1 , R 2 and Z are as defined in claim 1 , and
Q 1 is either absent or independently, at each occurrence, selected from the group consisting of aryl optionally substituted with one or two of C1-C6 alkyl, —OR 5 , —N(R 5 )R 5 , and halogen;
heteroaryl optionally substituted with one or two of C1-C6 alkyl, —OR 5 , —N(R 5 )R 5 and halogen;
and heterocyclyl optionally substituted with one or two of R 29 and R 30 ;
R 29 is either absent or independently, at each occurrence, selected from the group consisting of hydrogen, —OR 5 , halogen, —N(R 5 )R 5 , —NR 9 R 12 , —NH(C═O)R 5 , —(C═O)NH 2 , aryl, heteroaryl, heterocyclyl, and C1-C6 alkyl optionally substituted with —OH or —NH 2 ;
R 30 is, independently, at each occurrence, selected from the group consisting of hydrogen, halogen, —OR 5 , —N(R 5 )R 5 , (═O), aryl, heteroaryl, heterocyclyl, and C1-C6 alkyl optionally substituted with —OH or —NH 2 ;
wherein R 5 , R 9 and R 12 are as defined in claim 1 ;
L 2 is either absent or independently, at each occurrence, selected from the group consisting of —O—, —NH—, —(C═O)— and —(C═O)NH—;
Y 1 is, independently at each occurrence, selected from CH, C(OH) and N;
Y 2 is, independently at each occurrence, selected from CH, CR 30 , O and N;
m is, independently at each occurrence, selected from 0, 1 and 2;
n is, independently at each occurrence, selected from 0 and 1;
wherein, if R 1 is H, R 2 is CH(CH 3 ) 2 , L 1 is absent, Q 1 is absent, L 2 is absent, Y 1 is N, Y 2 is CH, m is 1, n is 1, R 29 is N(R 5 )R 5 , R 30 is H, R 5 is H, X is N, Z is phenyl, R 7 is H, R 8 is H, R 9 is H and R 10 is H, then R 6 is not 1H-pyrazole;
wherein, if R 1 is H, R 2 is CH(CH 3 ) 2 , L 1 is O, Q 1 is absent, L 2 is absent, Y 1 is CH, Y 2 is N, m is 1, n is 1, R 29 is CH 3 , R 30 is H, X is N, Z is phenyl, R 7 is H, R 8 is H, R 9 is H and R 10 is H, then R 6 is not 1H-pyrazole;
wherein, if R 1 is H, R 2 is CH(CH 3 ) 2 , L 1 is —(C═O)—, Q 1 is absent, L 2 is absent, Y′ is N, Y 2 is N, m is 1, n is 1, R 30 is H, X is N, Z is phenyl, R 6 is 1H-pyrazole, R 7 is H, R 8 is H, R 9 is H and R 10 is H, then R 29 is not H;
wherein, if R 1 is H, R 2 is CH(CH 3 ) 2 , L 1 is —(C═O)—, Q 1 is absent, L 2 is absent, Y 1 is N, Y 2 is CH, m is 1, n is 1, R 29 is N(R 5 )R 5 , R 30 is H, R 5 is H, R 30 is H, X is N, Z is phenyl, R 7 is H, R 8 is H, R 9 is H and R 10 is H, then R 6 is not 1H-pyrazole;
wherein, if R 1 is H, R 2 is CH(CH 3 ) 2 , L 1 is O, Q 1 is absent, L 2 is absent, Y 1 is CH, Y 2 is N, m is 1, n is 1, R 29 is H, R 30 is H, X is N, Z is phenyl, R 7 is H, R 8 is H, R 9 is H and R 10 is H, then R 6 is not 1H-pyrazole;
wherein, if R 1 is H, R 2 is CH(CH 3 ) 2 , L 1 is O, Q 1 is absent, L 2 is absent, Y 1 is CH, Y 2 is N, m is 1, n is 0, R 29 is H, R 30 is H, X is N, Z is phenyl, R 7 is H, R 8 is H, R 9 is H and R 10 is H, then R 6 is not 1H-pyrazole;
wherein, if R 1 is H, R 2 is CH(CH 3 ) 2 , L 1 is O, Q 1 is absent, L 2 is absent, Y 1 is CH, Y 2 is CH, m is 1, n is 1, R 29 is N(R 5 )R 5 , R 30 is H, R 5 is H, X is N, Z is phenyl, R 7 is H, R 8 is H, R 9 is H and R 10 is H, then R 6 is not 1H-pyrazole;
wherein, if R 1 is H, R 2 is CH(CH 3 ) 2 , L 1 is NH, Q 1 is absent, L 2 is absent, Y 1 is CH, Y 2 is N, m is 1, n is 0, R 29 is H, R 30 is H, X is N, Z is phenyl, R 7 is H, R 8 is H, R 9 is H and R 10 is H, then R 6 is not 1H-pyrazole;
wherein, if R 1 is H, R 2 is CH(CH 3 ) 2 , L 1 is absent, Q 1 is absent, L 2 is absent, Y 1 is N, Y 2 is CH, m is 1, n is 0, R 29 is N(R 5 )R 5 , R 30 is H, R 5 is H, X is N, Z is phenyl, R 7 is H, R 8 is H, R 9 is H and R 10 is H, then R 6 is not 1H-pyrazole;
wherein, if R 1 is H, R 2 is CH(CH 3 ) 2 , L 1 is NH, Q 1 is absent, L 2 is absent, Y 1 is CH, Y 2 is CH, m is 1, n is 1, R 29 is N(R 5 )R 5 , R 30 is H, R 5 is H, X is N, Z is phenyl, R 7 is H, R 8 is H, R 9 is H and R 10 is H, then R 6 is not 1H-pyrazole;
wherein, if R 1 is H, R 2 is CH(CH 3 ) 2 , L 1 is absent, Q 1 is absent, L 2 is absent, Y 1 is N, Y 2 is CH, m is 2, n is 0, R 29 is N(R 5 )R 5 , R 30 is H, R 5 is H, X is N, Z is phenyl, R 7 is H, R 8 is H, R 9 is H and R 10 is H, then R 6 is not 1H-pyrazole;
wherein, if R 1 is H, R 2 is CH(CH 3 ) 2 , L 1 is O, Q 1 is absent, L 2 is absent, V is CH, Y 2 is N, m is 2, n is 0, R 29 is H, R 30 is H, X is N, Z is phenyl, R 7 is H, R 8 is H, R 9 is H and R 10 is F, then R 6 is not 1H-pyrazole;
wherein, if R 1 is H, R 2 is CH(CH 3 ) 2 , L 1 is O, Q 1 is absent, L 2 is absent, Y 1 is CH, Y 2 is N, m is 1, n is 1, R 29 is CH 3 , R 30 is H, X is N, Z is phenyl, R 7 is H, R 8 is H, R 9 is H and R 10 is H, then R 6 is not 1H-pyrazole;
wherein, if R 1 is CH 3 , R 2 is CH(CH 3 ) 2 , L 1 is O, Q 1 is absent, L 2 is absent, Y 1 is CH, Y 2 is N, m is 2, n is 0, R 29 is H, R 30 is H, X is N, Z is phenyl, R 7 is H, R 8 is H, R 9 is H and R 10 is H, then R 6 is not 1H-pyrazole;
or an enantiomer, stereoisomeric form, mixture of enantiomers, diastereomer, mixture of diastereomers, racemate of the above compounds, or a pharmaceutically acceptable salt thereof.
5. The compound according to claim 1 , having the general formula IV
wherein X, and R 2 are as defined in claim 1 ;
wherein Q 1 is either absent or independently, at each occurrence, selected from the group consisting of aryl optionally substituted with one or two of C1-C6 alkyl, —OR 5 , —N(R 5 )R 5 , and halogen; heteroaryl optionally substituted with one or two of C1-C6 alkyl, —OR 5 , —N(R 5 )R 5 and halogen; and heterocyclyl optionally substituted with one or two of R 29 and R 30 ;
R 29 is either absent or independently, at each occurrence, selected from the group consisting of hydrogen, —Ole, halogen, —N(R 5 )R 5 , —NR 9 R 12 , —NH(C═O)R 5 , —(C═O)NH 2 , aryl, heteroaryl, heterocyclyl, C1-C6 alkyl and C1-C6 alkyl substituted with —OH or —NH 2 ;
R 30 is, independently, at each occurrence, selected from the group consisting of hydrogen, halogen, —OR 5 , —N(R 5 )R 5 , (═O), aryl, heteroaryl, heterocyclyl, C1-C6 alkyl and C1-C6 alkyl substituted with —OH or —NH 2 ;
L 2 is either absent or independently, at each occurrence, selected from the group consisting of —O—, —NH—, —(C═O)— and —(C═O)NH—;
Y 1 is, independently at each occurrence, selected from CH, C(OH) and N;
Y 2 is, independently at each occurrence, selected from CH, CR 30 , O and N;
m is, independently at each occurrence, selected from 0, 1 and 2;
n is, independently at each occurrence, selected from 0 and 1;
wherein Z 1 is
and wherein R 6 , R 7 , R 8 , R 9 and R 10 are as defined in claim 1 .
6. The compound according to claim 1 , having the general formula V
wherein X, X 1 , X 2 , L 1 , R 2 , R 6 , R 22 and R 23 are as defined in claim 1 ;
wherein Q 1 is either absent or independently, at each occurrence, selected from the group consisting of aryl optionally substituted with one or two of C1-C6 alkyl, —OR 5 , —N(R 5 )R 5 , and halogen; heteroaryl optionally substituted with one or two of C1-C6 alkyl, —OR 5 , —N(R 5 )R 5 and halogen; and heterocyclyl optionally substituted with one or two of R 29 and R 30 ;
R 29 is either absent or independently, at each occurrence, selected from the group consisting of hydrogen, —OR 5 , halogen, —N(R 5 )R 5 , —NR 9 R 12 , —NH(C═O)R 5 , —(C═O)NH 2 , aryl, heteroaryl, heterocyclyl, C1-C6 alkyl and C1-C6 alkyl substituted with —OH or —NH 2 ;
R 30 is, independently, at each occurrence, selected from the group consisting of hydrogen, halogen, —OR 5 , —N(R 5 )R 5 , (═O), aryl, heteroaryl, heterocyclyl, C1-C6 alkyl and C1-C6 alkyl substituted with —OH or —NH 2 ;
L 2 is either absent or independently, at each occurrence, selected from the group consisting of —O—, —NH—, —(C═O)— and —(C═O)NH—;
Y 1 is, independently at each occurrence, selected from CH, C(OH) and N;
Y 2 is, independently at each occurrence, selected from CH, CR 30 , O and N;
m is, independently at each occurrence, selected from 0, 1 and 2; and
n is, independently at each occurrence, selected from 0 and 1.
7. The compound according to claim 1 , having the general formula VI
wherein X, L 1 and R 2 are as defined in claim 1 ;
wherein Q 1 is either absent or independently, at each occurrence, selected from the group consisting of aryl optionally substituted with one or two of C1-C6 alkyl, —OR 5 , —N(R 5 )R 5 , and halogen; heteroaryl optionally substituted with one or two of C1-C6 alkyl, —OR 5 , —N(R 5 )R 5 and halogen; and heterocyclyl optionally substituted with one or two of R 29 and R 30 ;
R 29 is either absent or independently, at each occurrence, selected from the group consisting of hydrogen, —OR 5 , halogen, —N(R 5 )R 5 , —NR 9 R′2, —NH(C═O)R 5 , —(C═O)NH 2 , aryl, heteroaryl, heterocyclyl, C1-C6 alkyl and C1-C6 alkyl substituted with —OH or —NH 2 ;
R 30 is, independently, at each occurrence, selected from the group consisting of hydrogen, halogen, —OR 5 , —N(R 5 )R 5 , (═O), aryl, heteroaryl, heterocyclyl, C1-C6 alkyl and C1-C6 alkyl substituted with —OH or —NH 2 ;
L 2 is either absent or independently, at each occurrence, selected from the group consisting of —O—, —NH—, —(C═O)— and —(C═O)NH—;
Y 1 is, independently at each occurrence, selected from CH, C(OH) and N;
Y 2 is, independently at each occurrence, selected from CH, CR 30 , O and N;
m is, independently at each occurrence, selected from 0, 1 and 2;
n is, independently at each occurrence, selected from 0 and 1;
X 3 is, independently at each occurrence, selected from CR 10 and N;
R 26 , R 27 and R 28 are, at each occurrence, independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C1-C3 haloalkyl, —OR 5 , —CN and C1-C6 alkyl substituted with —OH, —OR 5 or —NHR 9 ;
R 5 , R 9 and R 10 are as defined in claim 1 ;
R 7 is any structure of the following group E;
and wherein R 8 and R 14 -R 20 are as defined in claim 1 .
8. The compound according to claim 1 , having the general formula VII
wherein X, L 1 , R 2 , R 6 , R 22 , R 23 , R 24 and R 25 are as defined in claim 1 ;
Q 1 is either absent or independently, at each occurrence, selected from the group consisting of aryl optionally substituted with one or two of C1-C6 alkyl, —OR 5 , —N(R 5 )R 5 , and halogen;
heteroaryl optionally substituted with one or two of C1-C6 alkyl, —OR 5 , —N(R 5 )R 5 and halogen;
and heterocyclyl optionally substituted with one or two of R 29 and R 30 ;
R 29 is either absent or independently, at each occurrence, selected from the group consisting of hydrogen, —OR 5 , halogen, —N(R 5 )R 5 , —NR 9 R 12 , —NH(C═O)R 5 , —(C═O)NH 2 , aryl, heteroaryl, heterocyclyl, C1-C6 alkyl and C1-C6 alkyl substituted with —OH or —NH 2 ;
R 30 is, independently, at each occurrence, selected from the group consisting of hydrogen, halogen, —OR 5 , —N(R 5 )R 5 , (═O), aryl, heteroaryl, heterocyclyl, C1-C6 alkyl and C1-C6 alkyl substituted with —OH or —NH 2 ;
L 2 is either absent or independently, at each occurrence, selected from the group consisting of —O—, —NH—, —(C═O)— and —(C═O)NH—;
Y 1 is, independently at each occurrence, selected from CH, C(OH) and N;
Y 2 is, independently at each occurrence, selected from CH, CR 30 , O and N;
m is, independently at each occurrence, selected from 0, 1 and 2; and
n is, independently at each occurrence, selected from 0 and 1.
9. The compound according to claim 1 , having the general formula VIII
wherein X, L 1 , R 2 , R 6 and R 10 are as defined in claim 1 ,
with the proviso that not both of R 6 and R 10 are hydrogen.
10. The compound according to claim 1 , having the general formula IX
wherein X is N; L 1 , R 2 , R 6 , R 22 , R 24 and R 25 are as defined in claim 1 , and X 3 is, independently at each occurrence, selected from CR 10 and N;
R 23 is selected from the group consisting of hydrogen, halogen, C1-C3 haloalkyl, —OR 5 , —CN and C1-C6 alkyl optionally substituted with —OH, or —OR 5 ;
wherein Q 2 is any structure of the following group F;
R 31 and R 32 are either absent or independently, at each occurrence, selected from the group consisting of hydrogen, —OR 5 , halogen, —N(R 5 )R 5 , —NR 9 R 12 , —NH(C═O)R 5 , —(C═O)NH 2 , aryl, heteroaryl, heterocyclyl, C1-C6 alkyl and C1-C6 alkyl substituted with —OH or —NH 2 ; and
wherein R 5 , R 9 and R 12 are as defined in claim 1 .
11. The compound according to claim 1 , having a structure selected from
#cpds
Structure
14
17
47
48
58
65
67
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80
81
90
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12. A pharmaceutical composition comprising a compound according to claim 1 , as an active ingredient, together with at least one pharmaceutically acceptable carrier, excipient and/or diluent.
13. A compound according to claim 1 for use as pharmaceutically active agent, wherein said pharmaceutically active agent has an inhibitory activity on cyclin-dependent kinase 7 (CDK7).
14. A method of treatment of a disease which is associated with inhibition of apoptosis, abnormal transcriptional activity and/or cell cycle arrest by aberrant activity and/or overexpression of one or several cyclin-dependent kinases (CDKs), wherein the disease is selected from proliferative diseases, infectious diseases, including opportunistic diseases, immunological diseases, autoimmune diseases, and inflammatory diseases and wherein the method comprises administering, to a subject in need of such treatment, a compound of claim 1 .
15. The method according to claim 14 , wherein the proliferative disease is a cancer selected from the group consisting of: adenocarcinoma, choroidal melanoma, acute leukemia, acoustic neurinoma, ampullary carcinoma, anal carcinoma, astrocytoma, basal cell carcinoma, pancreatic cancer, Desmoid tumor, bladder cancer, bronchial carcinoma, estrogen dependent and independent breast cancer, Burkitt's lymphoma, corpus cancer, Carcinoma unknown primary tumor (CUP-syndrome), colorectal cancer, small intestine cancer, small intestinal tumors, ovarian cancer, endometrial carcinoma, ependymoma, epithelial cancer types, Ewing's tumors, gastrointestinal tumors, gastric cancer, gallbladder cancer, gall bladder carcinomas, uterine cancer, cervical cancer, cervix, glioblastomas, gynecologic tumors, ear, nose and throat tumors, hematologic tumor, hairy cell leukemia, urethral cancer, skin cancer, skin testis cancer, brain tumors (gliomas), brain metastases, testicle cancer, hypophysis tumor, carcinoids, Kaposi's sarcoma, laryngeal cancer, germ cell tumor, bone cancer, colorectal carcinoma, head and neck tumors (tumors of the ear, nose and throat area), colon carcinoma, craniopharyngiomas, oral cancer (cancer in the mouth area and on lips), cancer of the central nervous system, liver cancer, liver metastases, leukemia, eyelid tumor, lung cancer, lymphomas, stomach cancer, malignant melanoma, malignant neoplasia, malignant tumors gastrointestinal tract, breast carcinoma, rectal cancer, medulloblastomas, melanoma, meningiomas, Hodgkin's/Non-Hodgkin's lymphoma, mycosis fungoides, nasal cancer, neurinoma, neuroblastoma, kidney cancer, renal cell carcinomas, oligodendroglioma, esophageal carcinoma, osteolytic carcinomas and osteoplastic carcinomas, osteosarcomas, ovarian carcinoma, pancreatic carcinoma, penile cancer, plasmacytoma, prostate cancer, pharyngeal cancer, rectal carcinoma, retinoblastoma, vaginal cancer, thyroid carcinoma, esophageal cancer, T-cell lymphoma, thymoma, tube carcinoma, eye tumors, urethral cancer, urologic tumors, urothelial carcinoma, vulva cancer, wart appearance, soft tissue tumors, soft tissue sarcoma, Nephroblastoma, cervical carcinoma, tongue cancer, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ, lobular carcinoma in situ, small-cell lung carcinoma, non-small-cell lung carcinoma, bronchial adenoma, pleuropulmonary blastoma, mesothelioma, brain stem glioma, hypothalamic glioma, cerebellar astrocytoma, cerebral astrocytoma, neuroectodermal tumor, pineal tumors, sarcoma of the uterus, salivary gland cancers, anal gland adenocarcinomas, mast cell tumors, pelvis tumor, ureter tumor, hereditary papillary renal cancers, sporadic papillary renal cancers, intraocular melanoma, hepatocellular carcinoma, cholangiocarcinoma, mixed hepatocellular cholangiocarcinoma, squamous cell carcinoma, malignant melanoma, Merkel cell skin cancer, non-melanoma skin cancer, hypopharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer, oral cavity cancer, squamous cell cancer, oral melanoma, AIDS-related lymphoma, cutaneous T-cell lymphoma, lymphoma of the central nervous system, malignant fibrous histiocytoma, lymph sarcoma, rhabdomyosarcoma, malignant histiocytosis, fibroblastic sarcoma, hemangiosarcoma, hemangiopericytoma, leiomyosarcoma (LMS), canine mammary carcinoma, and feline mammary carcinoma.
16. The method according to claim 14 , wherein the infectious disease is selected from the group consisting of AIDS, Adenovirus Infection, Alveolar Hydatid Disease (AHD), Amoebiasis, Angiostrongyliasis, Anisakiasis, Anthrax, Babesiosis, Balantidiasis, Baylisascaris Infection, Bilharzia (Schistosomiasis), Blastocystis hominis Infection, Lyme Borreliosis, Botulism, Brainerd Diarrhea, Brucellosis, Bovine Spongiform Encephalopathy (BSE), Candidiasis, Capillariasis, Chronic Fatigue Syndrome (CFS), Chagas Disease, Chickenpox, Chlamydia pneumoniae Infection, Cholera, Chronic Fatigue Syndrome, Creutzfeldt-Jakob Disease (CJD), Clonorchiasis, Cutaneous Larva migrans (CLM), Coccidioidomycosis, Conjunctivitis, Coxsackievirus A16 (Cox A16), Cryptococcal disease, Cryptosporidiosis, West Nile fever, Cyclosporiasis, Neurocysticercosis, Cytomegalovirus Infection, Dengue Fever, Dipylidium caninum Infection, Ebola Hemorrhagic Fever (EHF), Alveolar Echinococcosis (AE), Encephalitis, Entamoeba coli Infection, Entamoeba dispar Infection, Entamoeba hartmanni Infection, Entamoeba polecki Infection, Pinworm Infection, Enterovirus Infection (Polio/Non-Polio), Epstein Barr Virus Infection, Escherichia coli Infection, Foodborne Infection, Aphthae epizooticae, Fungal Dermatitis, Fungal Infections, Gastroenteritis, Group A streptococcal Disease, Group B streptococcal Disease, Hansen's Disease (Leprosy), Hantavirus Pulmonary Syndrome, Head Lice Infestation (Pediculosis), Helicobacter pylori Infection, Hematologic Disease, Hendra Virus Infection, Hepatitis (HCV, HBV), Herpes Zoster (Shingles), HIV Infection, Human Ehrlichiosis, Human Parainfluenza Virus Infection, Influenza, Isosporiasis, Lassa Fever, Leishmaniasis, Visceral leishmaniasis (VL), Malaria, Marburg Hemorrhagic Fever, Measles, Meningitis, Mycobacterium avium Complex (MAC) Infection, Naegleria Infection, Nosocomial Infections, Nonpathogenic Intestinal Amebae Infection, Onchocerciasis, Opisthorchiasis, Papilloma virus Infection, Parvovirus Infection, Plague, Pneumocystis Pneumonia (PCP), Polyomavirus Infection, Q Fever, Rabies, Respiratory Syncytial Virus (RSV) Infection, Rheumatic Fever, Rift Valley Fever, Rotavirus Infection, Roundworms Infection, Salmonellosis , Scabies, Shigellosis, Shingles, Sleeping Sickness, Smallpox, Streptococcal Infection, Tapeworm Infection, Tetanus, Toxic Shock Syndrome, Tuberculosis, duodenum, Vibrio parahaemolyticus Infection, Vibrio septicemia, Viral Hemorrhagic Fever, Warts, Waterborne infectious Diseases, Varicella-Zoster Virus infection, Pertussis and Yellow Fever.
17. The method according to claim 14 , wherein the immunological disease and/or autoimmune disease is selected from the group consisting of: asthma, diabetes, rheumatic diseases, AIDS, rejection of transplanted organs and tissues, rhinitis, chronic obstructive pulmonary diseases, osteoporosis, ulcerative colitis, sinusitis, lupus erythematosus, recurrent infections, atopic dermatitis/eczema and occupational allergies, food allergies, drug allergies, severe anaphylactic reactions, anaphylaxis, manifestations of allergic diseases, primary immunodeficiencies, antibody deficiency states, cell mediated immunodeficiencies, severe combined immunodeficiency, DiGeorge syndrome, Hyper IgE syndrome (HIES), Wiskott-Aldrich syndrome (WAS), ataxia-telangiectasia, immune mediated cancers, white cell defects, autoimmune diseases, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), multiple sclerosis (MS), immune-mediated or Type 1 Diabetes Mellitus, immune mediated glomerulonephritis, scleroderma, pernicious anemia, alopecia, pemphigus, pemphigus vulgaris, myasthenia gravis, inflammatory bowel diseases, Crohn's disease, psoriasis, autoimmune thyroid diseases, Hashimoto's disease, dermatomyositis, Goodpasture syndrome (GPS), myasthenia gravis (MG), Sympathetic ophthalmia, Phakogene Uveitis, chronical aggressive hepatitis, primary biliary cirrhosis, autoimmune hemolytic anemia, and Werlhof's disease.
18. The method according to claim 14 , wherein the inflammatory disease is caused, induced, initiated and/or enhanced by bacteria, viruses, prions, parasites, fungi, and/or caused by irritative, traumatic, metabolic, allergic, autoimmune, or idiopathic agents.
19. The method according to claim 14 , wherein the inflammatory disease is selected from the group consisting of inflammatory diseases of the central nervous system (CNS), inflammatory rheumatic diseases, inflammatory diseases of blood vessels, inflammatory diseases of the middle ear, inflammatory bowel diseases, inflammatory diseases of the skin, inflammatory disease uveitis, and inflammatory diseases of the larynx.
20. The method according to claim 14 , wherein the inflammatory disease is selected from inflammatory diseases of the central nervous system (CNS), inflammatory rheumatic diseases, inflammatory diseases of blood vessels, inflammatory diseases of the middle ear, inflammatory bowel diseases, inflammatory diseases of the skin, inflammatory disease uveitis, inflammatory diseases of the larynx, wherein preferably said inflammatory diseases are selected from the group comprising abscessation, acanthamoeba infection, acne vulgaris, actinomycosis, acute inflammatory dermatoses, acute laryngeal infections of adults, acute multifocal placoid pigment epitheliopathy, acute (thermal) injury, acute retinal necrosis, acute suppurative otitis media, algal disorders, allergic contact dermatitis, amyloidosis angioedema, ankylosing spondylitis, aspergillosis, atopic dermatitis, pseudorabies, autoantibodies in vasculitis, bacterial disorders, bacterial laryngitis, bacterial meningitis, Behcet's disease (BD), birdshot choroidopathy, Gilchrist's disease, Borna disease, brucellosis, bullous myringitis, bursitis, candidiasis, canine distemper encephalomyelitis, canine distemper encephalomyelitis in immature animals, canine hemorrhagic fever, canine herpes virus encephalomyelitis, cholesteatoma, chronic granulomatous diseases (CGD), chronic inflammatory dermatoses, chronic relapsing encephalomyelitis, chronic suppurative otitis media, Ocular Cicatricial pemphigoid (OCP), common upper respiratory infection, granuloma, Crohn's disease, cryptococcal disease, dermatomyositis, diphtheria, discoid lupus erythematosus (DLE), drug-induced vasculitis, drug or hypersensitivity reaction, encephalitozoonosis, eosinophilic meningoencephalitis, Erythema multiforme (EM), feline leukemia virus, feline immunodeficiency virus, feline infectious peritonitis, feline Polioencephalitis, feline spongiform encephalopathy, fibromyalgia, Fuchs Heterochromic Uveitis, gastroesophageal (laryngopharyngeal) reflux disease, giant cell arteritis, glanders, glaucomatocyclitic crisis, gonorrhea granular myringitis, Granulomatous meningoencephalitis (GME), herpes simplex, histoplasmosis, idiopathic diseases, idiopathic inflammatory disorders, immune and idiopathic disorders, infections of the immunocompromised host, infectious canine hepatitis, inhalation laryngitis, interstitial nephritis, irritant contact dermatitis, juvenile rheumatoid arthritis, Kawasaki's disease, La Crosse virus encephalitis, laryngeal abscess, laryngotracheobronchitis, leishmaniasis, lens-induced uveitis, leprosy, leptospirosis, leukemia, lichen planus, lupus, lymphoma, meningitis, meningoencephalitis in greyhounds, miscellaneous meningitis/meningoencephalitis, microscopic polyangiitis, multifocal choroiditis, multifocal distemper encephalomyelitis in mature animals, multiple sclerosis, Muscle Tension Dysphonia (MTD), mycotic (fungal) diseases, mycotic diseases of the CNS, necrotizing encephalitis, neosporosis, old dog encephalitis, onchocerciasis, parasitic encephalomyelitis, parasitic infections, Pars planitis, parvovirus encephalitis, pediatric laryngitis, pollution and inhalant allergy, polymyositis, post-vaccinal canine distemper encephalitis, prion protein induced diseases, protothecosis, protozoal encephalitis-encephalomyelitis, psoriasis, psoriatic arthritis, pug dog encephalitis, radiation injury, radiation laryngitis, radionecrosis, relapsing polychondritis, Reiter's syndrome, retinitis pigmentosa, retinoblastoma, rheumatoid arthritis, Rickettsial disorders, rocky mountain spotted fever, salmon poisoning disease (SPD), Sarcocystosis, sarcoidosis, schistosomiasis, scleroderma, Rhinoscleroma, serpiginous choroiditis, shaker dog disease, Sjogren's syndrome, spasmodic croup, spirochetal (syphilis) diseases, spongiotic dermatitis, sporotrichosis, steroid responsive meningitis-arteritis, Stevens-Johnson syndrome (SJS, EM major), epiglottitis, sympathetic ophthalmia, Syngamosis, syphilis, systemic vasculitis in sarcoidosis, Takayasu's arteritis, tendinitis (tendonitis), Thromboangiitis obliterans (Buerger Disease), tick-borne encephalitis in dogs, toxic epidermal necrolysis (TEN), toxocariasis, toxoplasmosis, trauma, traumatic laryngitis, trichinosis, trypanosomiasis, tuberculosis, tularemia, ulcerative colitis, urticaria (hives), vasculitis, vasculitis and malignancy, vasculitis and rheumatoid arthritis, vasculitis in the idiopathic inflammatory myopathies, vasculitis of the central nervous system, vasculitis secondary to bacterial, fungal, and parasitic infection, viral disorders, viral laryngitis, vitiligo, vocal abuse, vocal-cord hemorrhage, Vogt-Koyanagi-Harada syndrome (VKH), Wegener's granulomatosis, and Whipple's disease.Cited by (0)
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